title: Combined antiretroviral therapy and immune pressure lead to in vivo HIV-1 recombination with ancestral viral genomes.
abstract: BACKGROUND
  Studies on drug interruption have provided new insights on the adaptive evolution of rebounding HIV-1 during antiretroviral pressure. We investigated the origin of new viral variants after discontinuation of protease (PR) inhibitors as a treatment remained exclusively based on reverse transcriptase inhibitors, and whether drug susceptibility, viral fitness, and neutralizing antibodies could be major driving forces for the evolution of virus populations.
  
  
  METHODS
  The study comprised 3 treatment-experienced subjects. Phylogenetic analysis of the PR, reverse transcriptase, and the viral envelope were carried out to ascertain the origin of the new viral variants with samples obtained over a 10-year period before and after a PR inhibitor withdrawal. In addition, drug susceptibility, replication capacity, and neutralization assays were performed.
  
  
  RESULTS
  New viral variants from all 3 subjects were derived through recombination with ancestral quasispecies. Computerized recombination models confirmed these results. Recombination was demonstrated by increased replication capacity, decreased drug susceptibility, and neutralization of ancestral virus envelope by contemporaneous plasma samples.
  
  
  CONCLUSIONS
  These findings demonstrate the relevance of HIV-1 reservoirs in adaptive evolution throughout recombination in response to selective pressure, such as antiretroviral therapy and immune responses. This result might assist in the design of new treatment strategies for patients experiencing treatment failure.
authors.affiliation: Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Buzón
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Codoñer
authors.forename: Judith
authors.initials: J
authors.lastname: Dalmau
authors.forename: Pham
authors.initials: P
authors.lastname: Phung
authors.forename: Anna
authors.initials: A
authors.lastname: Bonjoch
authors.forename: Eoin
authors.initials: E
authors.lastname: Coakley
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D005075:Biological Evolution; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D016679:Genome, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D009500:Neutralization Tests; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D016865:Reassortant Viruses / Q000187:drug effects / Q000235:genetics; D011995:Recombination, Genetic / Q000187:drug effects / Q000276:immunology; D012189:Retrospective Studies; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral